Delta8-bisnorallocholenates



' M-BISNORALLOCHOLENATES Earl M. Chamberlin, Westfield, and John M. Chemerda, Metuchen, N. J.,'assignors to Merck & Co., Inc., Rahway, N. J.,*a corporation of New Jersey No Drawing. Original application September 20, 1951,

Serial No. 247,562. Divided and this application November 26, "1957, Serial N0. 703,720

2 Claims. (Cl. 260-3971) This application is a division of copending applications Serial No. 215,026, filed March 10, 1951, now abandoned, and Serial No. 247,562, filed September 20, 1951. i

This invention is concerned with novel chemical compounds of the cyclopentanopolyhydrophenanthrene series and processes for preparing the, same; more particularly, it relates to' novel cyclopen tanopolyhydrophenanthrene compounds having functional substituents in ring C; and specifically it relates to new compounds having a hydroxyl or keto substitutent at the 11 position, and to processes for the preparation of such compounds.

Compounds of the adrenal cortex, such as ,Kendalls Compound E (cortisone), have been found'to be of great value in the treatment'of various'diseases. Further, it is' likely that Kendalls Compound E and/or other'closely related l l-hydroxy steroids will find increasing therapeu-' tic use in the future. Unfortunately, the only method for the preparation of such compounds presently available utilizes desoxycholic or cholic acids as the starting material. Cholic and desoxycholic acids have hydroxy substituents in ring C at the 12 position, thus providing a means for introducing a functional substituent at the 11 position. However cholic and desoxycholic acids, which are obtained from animal bile, are only available in limited amounts. Heretofore no practical method was available whereby a functional group could be introduced in ring .C which would permit the use of more abundant steroids such as the sterols, ergosterol, cholesterol, stigmasterol, or plant sapogenins, such as diosgenimtigogenin, and the like.

it is an object of the present invention to provide a proc- V ess for introducing a functional group in ring Cat, the 11 position. It, is a further object to provide, a process for converting cyclopentanopolyhydrophenanthrene compounds'having'a .double bond in the 7:8 position to the corresponding cyclopentanopolyhydrophenanthrene compound having a hydroxyl or keto group at positions 7 and .11. Another object is to provide new compounds; of

the steroid series having functional groups in ring C suitable for the preparation ofother 'cyclopentanopolyhydrophenanthrene compounds? Other objects will be apparent from the detailed description hereinafter provided; I

Inaccord'anc'e'with our invention, we have now found that compounds of the cyclopentanopolyhydrophenanthrene series havingan ll keto substituent can be synthesizedgbygreactions indicated as follows resented by the alternate Formulas IIIA and IIIB.

7 Patented Sept. 16, 1958' IIIB VII

- These reactions are carried out as follows:

A cyclopentanopolyhydrophenanthrene compound having a 7:8 double bond (1) is reacted with mercuric acetate producing the corresponding compound having conjugated double bonds in the 7:8 and 9:11 positions (II) which is treated with a per acid, thus'forming an epoxide rep-.

(At present the exact structure of the epoxide is not known and it is represented by the alternative forms IIIA and IIIB. Alternatively it is possible that the product obtained is a mixture of these two forms.) This epoxide is vthen treated with an adsorbent to form the corresponding A -7,l1dihydroXy compound (IV).

The A -7,11-dihydroxy compound (IV) is reacted with an oxidizing agent to convert the hydroxy'substituents to keto groups, thus obtaining the corresponding A -7,11- diketo cyclopentanopolyhydrophenanthrene derivatives (V). These diketo compounds are then reduced to saturate the A 'double bond and form the corresponding 7,11-diketo compound VI. The saturated diketo compound is then reduced to eliminate the 7-keto substituent, thus producing 'the corresponding ll-keto compound (VII). The latter compounds are useful intermediates for the preparation of ll-keto compounds having desirable therapeutic properties.

The E -compounds of the cyclopentanopolyhydrophenanthrene series are conveniently prepared by reacting the corresponding A' compound with mercuric acetate. We have found that this reaction is preferably eifected by reacting the A -compound with mercuric acetate and glacial acetic 'acid in the presence of a suitable solvent medium such as chloroform. The reaction is conveniently conducted by stirring the reaction mixture for 16-24 hours. After the reaction is completed, the A a -compound is recovered from the reaction mixture by removing the precipitated mercurous acetate, and concentrating the solution under diminished pressure. If

desired, the residue may be further purified by crystallization from suitable solvents. Thus, this process can be utilized to prepare A -pregnadiene-3-ol-20-one-3- acetate, and A -dehydrotigogenin acetate from A pregn-enolone acetate and A' -dehydrotigogenin acetate respectively. Alternatively, other acyl derivatives of these starting materials or the 3-hydroxy compounds may be utilized as starting materials in our process to prepare the corresponding A -compounds.

Further, the 3-hydroxy-A -choladienic acid, which is also useful as a starting material in the processes of our invention, is readily obtained by reducing B-hydroxy- 12-keto-A' -choladienic acid. This is conveniently accomplished by reacting the keto acid with hydrazine hydrate and an alkali metal hydroxide in the presence of a suitable high boiling solvent such as diethylene glycol.

This invention is concerned with compounds of the type represented by intermediates V and VI above, and with processes of producing the same. Compounds V and VI may be represented by the following formulas:

The starting materials used in the process of this invention, namely the n -dihydroxy compounds shown by Formula IV, may be obtained as described in copending application Serial No. 215,026, now abandoned, filed March 10, 1951.

Pursuant to our invention, we have found that the A -7,11-dihydroxy compounds are readily oxidized to obtain a new series of compounds having a double bond in the 8:9 position and keto substituents in the 7 and 11 positions. This oxidation is readily accomplished for example by treating the A -7,11-dihydroxy compounds with chromic acid in the presence of an acid such as acetic or sulfuric acid. We have found that an oxidation mixture consisting of chromic acidacetone-sulfuric acid is particularly useful for this oxidation, and results in the obtainment of maximum yields of the desired diketo compound under optimum conditions. In carrying out this process, it is necessary to protect any other hydroxyl substituents, for example, a 3-hydroxy group, by converting this group to an acyloxy substituent. After the oxidation, any such acyloxy substituents can be readily hydrolyzed to prepare the corresponding hydroxy compounds.

These new A -7,11-diketocyclopentanopolyhydrophenanthrene compounds are reduced to saturate the 8:9 double bonds and produce the corresponding saturated 7.11-diketo compound. This reduction is conveniently accomplished for example by reacting the A compound with zinc in the presence of acetic acid.

In accordance with the above-described methods, cyclopentanopolyhydrophenanthrene compounds having 7,11 diketo substituents such as, 3-acyloxy-7,11-diketo-A ergostadiene, 3-acyloxy-7, l 1-diketo-A -bisnorallocholenic acid and its esters, 3-acyloxy-7,1l-diketo-n -cholenic acid and its esters, 3-acylox -7,1l-diketo-n -tigogenin, A -allopregnene-3-ol-7,11-20-trione and its acyl derivatives, and the like can be obtained by the oxidation of the corresponding 7,11-dihydroxy compounds. Further, these diketo compounds may be reduced to the corresponding compounds having a saturated bond in the 8:9 position.

The following examples are presented to illustrate specific embodiments of our invention.

EXAMPLE 1 Preparation of 3-tzce2oxy-7J1diketo-A -erg0s!adiene from 3-acet0xy7,1.7-dihydroxy-A erg0smdiene Two hundred milligrams of 3-acetoxy-7,1l-dihydroxy- 4 A -ergostadiene suspended in 10 cc. of acetic acid was treated with mg. of sodium dichromate. With gentle swirling, the product dissolved rapidly, the resulting green solution was diluted with water, and a gummy product separated which was extracted with benzene. The residue obtained after the removal of the benzene in vacuo crystallized readily from methanol in the form of compact rosettes of small needles. Yield: 40 mg.

M. P. 121-123 C.; A max. 2650 A., E% 147. Further purification by chromatography over alumina yielded pure 3-acetoxy-7,l1-diketo-A -ergostadiene; M. P. 136 C.

Analysis-Cale. for C H 4O C, 76.88; H, 9.46. Found: C, 76.91; H, 9.58. Max. 2660 A. (E% 200--isooctane). Max. 2700 A. (E% 186-et.hanol). a +18i2 (1% CI-ICI EXAMPLE 2 Preparation of 3-acet0xy-7,11-diketo-A -erg0stqdiene from 3-acetoxy-7J 1-dihydr0xy-A -erg0stadiene To a stirred suspension of 2.36 g. of 3-acetoxy-7,1ldihydroxy-A -ergostadiene in 50 ml. of purified acetone was added a solution of 6.65 millimols of chromic oxide in 5 ml. of 3.6 N sulfuric acid. The mixture was stirred at 10 C. for 10 minutes, after which 2 ml. water was added, and the mixture was stirred for 25 minutes at room temperature. The green inorganic material which had separated was removed by filtration. The filtrate was stirred while 50 ml. water were added. The product was collected on a filter and washed with water. After drying in vacuo over phosphorous pentoxide the product, 3-acetoxy-7,11diketo-A -ergostadiene, was obtained in the form of a light yellow powder. 103 ll4 C. A max. 2 660 (E% l21etl1anol).

EXAMPLE 3 Preparation of 3-acet0xy-7,Z1-dikef0-A ?-erg0stene from 3 -acet0xy-7,] 1diketo-A -ergostadiene A hot solution of 100 mg. of 3-acetoxy-7,l1-diketo- A -ergostadiene in 5 cc. of acetic acid and 0.1 cc. of water was treated with 250 mg. of zinc. The initially yellow solution was decolorized rapidly and the mixture heated on the steam bath for three hours. Water was then added to precipitate the diketone, which was dissolved in benzene. residue was obtained which was recrystallized from methanol. Yield: 70 mg.; M. P. 196-198 C.; at 25 (1.0% CHCl;,). 7 a

Analysis.-Calc. for C H O C,. 76.55; H, 9.85. Found: C, 76.68; H, 9.59. 2

-Alkaline hydrolysis of 3-acetoxy-7,11-diketo-A -ergos tene yielded 3-hydroxy-7,1l-diketo-n -ergostene, M. P. 198199 C.

ArzaIysis.Calc. for C H O C, 78.46; H, 10.37.

Found; C, 78.28; H, 10.09.

EXAMPLE 4 To a stirred solution of 1.60 g. of methyl 3-acetoxy- 7,11-dihydroxy-A -bisnorallocholenate in 30 ml. of glacial acetic acid,was added a solution of 0.730 g. of sodium dichromate dihydrate in 30 ml. of glacial acetic acid over a period of 15 minutes. After stirring at 25 C. for two hours, the mixture was concentrated in vacuo to a small volume. The residue was shaken with 50 ml. of benzene and 50 ml. of water. The aqueous layerwas extracted twice with 25 ml. portions of benzene. The combined benzene extracts were washed with 50 ml. of water, dried over anhydrous sodium sulfate, and the benzene was removed by vacuum distillation. The residual oil was triturated with 3 m1. of cold methanol and Yield: 2.26 g., M. P;

Upon removal of the benzene, a

5 g. of methyl 3-acetoxy-7,11-diketo'bisnorallochola nate (III) and 2.07 g. of powdered potassium hydroxide were placed in a 50 cc. round-bottom flask. 25cc. of diethylene glycol and 2.3. cc. of 85% hydrazine. hy-

drate were added and the temperature raised to 130-140 C. and held for 1 hour. The-temperature wasthen raised to 195-200 C. and held for 2 hours.

After cooling, the reaction mixture was-dissolved in Methyl 3-hydr0xy-1I-keto-bisnorallocholanate COOH One gram of 3-acetoxy-7,ll-diketo-A -ergostene (I) obtained as described in Example 3 was dissolved in 100 cc. of chloroform and ozone was passed through at ice bath temperature until the approximate theoretical amount of ozone was absorbed. The reaction mixture was diluted with 100 cc. of glacial acetic acid, cooled to 5 C. and oxidized with 0.5 g.'chromic acid dissolved in 0.75 cc. water and 50 cc. glacial acetic acid.

After standing overnight, 5 cc. of methanol was added and the solvent was removed in vacuo to practically dryness. The residue in the flask was dissolved by shaking twice with a mixture of cc. of 5% sulfuric acid and 50 cc. of benzene. The combined benzene solutions were dried over anhydrous magnesium sulfate, and

the benzene was evaporated on the steambath in a stream of nitrogen. r

The residue was dissolved in 200 cc. of ether and stirred with 5 g. of sodium carbonate and 2 cc. of water for 21 hours. The sodium salt of 3-acetoxy-7,l1-diketobisnorallocholanic acid (II) was filtered off and dried in a vacuum desiccator. I

The dried sodium salt was suspended in 25 cc. of ether and 25 cc. of sulfuric acid was added in small portions until the mixture was definitely acid. 100 cc. of ether was added to bring about complete solution of all solids. The aqueous layer was separated and extracted once with 50 cc. of ether.

The combined ethereal solutions were dried over anhydrous magnesium'sulfate and then evaporated on the steam bath to a small volume, whereupon 3-acetoxy-7,1ldiketo-bisnorallocholanic acid (II) crystallized out. The product was recrystallized from ether; M. P. 235238 C. [a] =24.6; oc=0.68; C=1.38% CHCl Analysis.Calcd. for C H O C, 68.87; H, 8.19.

Found: C, 68.67; H, 8.04.

125 mg. of 3-acetoxy-7,l1-diketo-bisnorallocholanic acid was suspended in 25 cc. of ether and esterified with diazomethane. All solid dissolved and on evaporation of the ether to a small volume, the methyl ester (III) crystallized. M. P. 226.5229 C. Mixed melting point with an authentic sample of the ester: 227-230" C.

COOC

IV benzene and water, 50% sulfuric acid added until an acid reaction was obtained The benzene layer was separated, and the aqueous layer extracted three times with 50 cc. of benzene. The combined benzene solutions were washed with water and dried over anhydrous magnesium sulfate. 7 V 1 The benzene was treated with Darco. The benzene solution was concentrated in vacuo to dryness, the residue was dissolved in ether and esterified with an ethereal solution of diazomethane. The ether was evaporated, and the methyl 3-hydroxy-11-keto bisnorallocholanate (IV) was recrystallized from methanol, M. P. 1775- 180.5. Mixed M. P. with an authentic sample, 177-179 C. [oc] =|-41.

- EXAMPLE 6 Preparation of methyl 3-acet0xy-7,1l-diketo-bisnorallocholanate from methyl 3-acetoxy-7,1I-diketo-A -bisnorallocholenate A mixture of 400 g. of methyl 3-acetoxy-7,1l-diketo- A -bisnorallocholenate, 20 ml. of glacial acetic acid, 0.4 ml. water, and 1.5 g. zinc dust was heated for one hour on the steam bath. One gram of zincdust was added, and the mixture was heated for two hours more. After cooling to room temperature, 50 ml. water were added to the mixture. The precipitated product, along with residual zinc, was collected on a filter. The dried mixture was extracted with benzene. After removal of the benzene by vacuum distillation, the product, methyl 3- acetoxy-7,11-diketo-bisnorallocholanate was recrystallized from methanol. Yield: 270 mg.; M. P. 230-2315 C. The analytical sample was recrystallized from methanol, M. P. 2305-2315 C. [111 -14.5 (C=1.55, CHCla).

Analysis.Calc. for C H O C, 69.41; H, 8.39. Found: C, 69.70; H, 8.40.

EXAMPLE 7 Preparation of methyl 3-acetoxy-7,11-diket0-A -ch0leriate from methyl 3-acetoxy-7,1l-dihydroxy-A -cholenate To a stirred suspension of 1.7 g. of methyl 3-acetoxy- 7,1l-dihydroxy-A -cholenate in cc. acetone was added at 20 C. with stirring a solution of 0.5 g. chromium trioxide in 4 cc. of 10% sulfuric acid over a period of ten minutes. After addition was complete, the mixture was stirred for one and one half hours. The inorganic residue was filtered off and washed with three 10 cc. portions of acetone. The acetone solution was added with stirring to 66 cc. Water and the 7,11-diketo compound which precipitated was filtered, washed free of acid with water and dried. Yield: 1.57 g.; M. P. 112.5113.5 C.

After recrystallization from ethanol the product, methyl 3-acetoxy-7,1l-diketo-A -cholenate melted at 1l4ll5 C.

Analysiis.Calc. for C27H40O5I C, 70.40; H, 8.75. Found: C, 70.93; H, 8.30.

xgg 2715; 121% 187 EXAMPLE 8 Preparation of methyl 3-acet0xy-7,1l-diketo-c/zolanate from methyl 3-acet0xy-7,1l-diketo-A -cholenate A mixture of 1.57 g. of methyl 3-acetoxy-7,11-diketo- M-cholenate, 17 cc. acetic acid, 1.7 cc. water and 3.4 g. zinc dust was heated on a steam bath for one hour.

The reaction mixture was diluted with 80 cc. benzene and the zinc residue was filtered off. The benzene solution was washed free of acid with water, dried over anhydrous sodium sulfate and concentrated to dryness. Yield 1.57 g.

The product was purified by recrystallization from ethanol. Yield: 1.17 g.; M. P. 1623 C.

Analysis.Calc. for C27H42O6I C, 70.10; H, 9.15. Found: C, 70.52; H, 8.65.

EXAMPLE 9 Preparation of 3-Zzcet0xy-7J1-diketo-8-dehydr0tigogenin from 3-acetoxy-7,11-dihydroxy-8-dehydr0tigogenin To a suspension of 0.346 g. (0.71 millimol) of 3- acetoxy-7,11-dihydroxy-8-dehydrotigogenin in 10 ml. of acetone was added 0.8 ml. of a solution of 1.06 millimols of chromium trioxide in 3.6 N sulfuric acid. After stirring for 15 minutes, the chromium salts which had formed were removed by filtration and were washed with ml. of acetone. The filtrate was treated with 5060 ml. of water to precipitate the product which, after drying, weighed 0.283 g., M. P. 190200 C. After two'recrystallizations from methanol, 3-acetoxy-7,1l-diketo-S-dehydrotigogenin was obtained as pale yellow needles, M. P. 226227 C. [M -14 (c.=0.8l3, CHC1 )t max. (in ethanol) 2700,

8 EXAMPLE 10 Preparation of 3-acetoxy-7J l-dz'ketotigogenin from 3 acetoxy-7,I 1 -diket0-8-dehydroiigogenin A mixture of mg. of 3-acetoxy-7,11-diketo-8-dehydrotigogenin, 4 ml. glacial acetic acid, one drop of water, and 400 mg. of zinc dust was heated on the steam 'bath for one hour. The mixture was cooled,.and 30 ml. of water and 20 ml. of chloroform were added. After shaking thoroughly and filtering, the layers were separated, and the aqueous layer was extracted twice with five ml. portions of chloroform. The combined chloroform extracts were dried over sodium sulfate, and concentrated in vacuo. Recrystallization of the residue gave small rectangular prisms. Yield 75 mg., M. P. 241-243 C., [111 72 (c.=0.827, CHCl EXAMPLE 11 Preparation of M-allopregnene-3-0l-7J1,20-tri0ne-3-acetaze from A -allopregnene-3,7,l1-tri0l-20-one-3-acetwte Seven hundred and eighty milligrams of A -allopregnene-3,7,11-trio1-20-one-3-acetate in 20 ml. of acetone were oxidized with 2.66 millimols of chromium trioxide in 2 ml. of 10% aqueous sulfuric acid. After isolating the product in the usual way, it was recrystallized from methanol to give 260 mg. of pale yellow prisms, M. P. 177179 C., +71 (c.=1.12, 12 CHCl A max. 2690,

EXAMPLE 12 Preparation of all0pregnan-3-al-7,11,,20-trione-3-acetate from M-allopregnene-3-0l-7,]1,20-tri0ne-3-acetaze A mixture of 210 mg. of A allopregnene-3-ol-7,11, 20-trione-3-acetate, 10 ml. of glacial acetic acid, two drops of Water, and 1.0 g. of zinc dust was heated on the steam bath for 1 hour. The product was isolated in the usual manner, and recrystallized from methanol to give mg. of hexagonal prisms, M. P. 214215 C.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. Lower alkyl esters of 3-acyloxy-7,ll-diketo-A -bisnorallocholenic acid 'wherein the acyl substituent is a lower fatty acid radical.

2. Methyl 3-acetoxy-7,11-diketo-A bisnorallocholenate.

No references cited. 

1. LOWER ALKYL ESTERS OF 3-ACYLOXY-7,11-DIKETO-$8-BIS NORALLOCHOLENIC ACID WHEREIN THE ACYL SUBSTITUENT IS A LOWER FATTY ACID RADICAL. 